Asymmetric Imine Hydrogenation Processes

ABSTRACT

A process for the catalytic hydrogenation or asymmetric hydrogenation of imines of Formula (I) to the corresponding amines of Formula (II) is provided in which R 1  is aryl; R 2  is aryl, cyclic, alkyl, alkenyl or alkynyl; and R 3  is alkyl. The catalytic system includes a ruthenium complex containing (1) a diamine and (2) a diphosphine or two monodentate phosphines ligands. Such process also relates to the asymmetric hydrogenation of prochiral imines to the chiral amines using chiral ruthenium complexes bearing chiral diphosphines or chiral monodentate phosphines and chiral diamines.

FIELD OF THE INVENTION

The present invention relates to the field of catalytic hydrogenations,particularly catalytic asymmetric hydrogenation processes of thereduction of imines to amines in which the catalytic system includes aruthenium complex containing (1) a diamine and (2) a diphosphine or twomonodentate phosphines ligands.

BACKGROUND OF THE INVENTION

There is continuously a growing demand for enantiomerically pure aminesin the pharmaceutical, agrochemical and fine chemicals industries. Overthe past decade, there has been significant efforts directed towardsdeveloping procedures for asymmetric imine hydrogenations. Although manyhighly enantioselective chiral catalysts and catalytic processes areavailable for the asymmetric hydrogenation and transfer hydrogenation ofC═C and C═O bonds, there are only a few widely applicable and feasibleprocesses for effective reduction of the analogous C═N function ofimines. The production of chiral amines via this methodology stillrepresents a major challenge.

In 1997, B. R. James reviewed the preparation of chiral amines byhomogeneous catalytic hydrogenation reactions involving metal complexes(James, Catalysis Today 1997, 37, 209-221). The review by James namesseveral systems based on rhodium for the asymmetric hydrogenation ofimines but they suffer from drawbacks, such as low enantioselectivity orsevere reaction conditions. In U.S. Pat. No. 6,037,500, X. Zhang et al.disclosed the use of BICP, a chiral diphosphine ligand, on rhodium andiridium in the asymmetric hydrogenation of internal C═N bonds at 1000psi H₂ at room temperature to produce amines with e.e. ranging from 65to 94%. Spindler and co-workers demonstrated the use of in situgenerated iridium JOSIPHOS complexes for the enantioselectivehydrogenation of imines (Spindler et al., Angew. Chem., Int. Ed. Engl.,1990, 29, 558; Blaser and Spindler, Topics in Catalysis, 1997, 4, 275).This process was subsequently modified and applied to the industrialproduction of the imine precursor to (S)-Metolachlor, a valuableagrochemical product, then for Ciba-Giegy, now for Novartis. Theproduction of S-Metolachlor is an example of a large-scale industrialprocess that depends on the homogenous hydrogenation of a prochiralimine.

Buchwald and co-workers prepared and effectively employed various chiralansa-titanocene complexes for both hydrogenation and hydrosilylation ofimlines (Willoughby and Buchwald, J. Am. Chem. Soc., 1992, 114, 7562; J.Am. Chem. Soc., 1994, 116, 8952 and 11703). The need to activate thecatalyst by the addition of butyl-lithium and phenyl silane limits thescope and applicability of this process. This system also suffers fromthe drawback of being very oxygen and water sensitive.

A recent article by Tang and Zhang provides a comprehensive review onother advances in enantioselective hydrogenation of imines (Tang andZhang, Chem. Rev. 2003, 103, 3029). These include several recentexamples of the development and use of chiral complexes of rhodium(Buriak et al., Organometallics 1996, 15, 3161; Spindler et al., Adv.Synth. Catal. 2001, 343, 68), iridium (Bianchini et al., Organometallics1998, 17, 3308; Kainz et al., J. Am. Chem. Soc., 1999, 121, 6421; Zhanget al., Angew. Chem. Int. Ed. Engl. 2001, 40, 3425) and palladium (Abeet al., Org. Lett. 2001, 3, 313) and their use for the asymmetrichydrogenation of various cyclic and acyclic imines.

Despite the reported successes of some of these catalytic hydrogenationprocesses for imines, there are certain significant drawbacks. Theseinclude high operating pressures (typically >50 bar H₂), high catalystloading and the use of expensive iridium- and rhodium-based systems. Inaddition, activity and/or enantioselectivity tends to be either low orhighly substrate dependent, which in some cases necessitates thedevelopment of an entire catalytic system and process for only onesubstrate or a very closely related group of substrates.

Recently Rautenstrauch et al. reported the use of metal complexes withP—N bidentate ligands (WO 02/22526 A2) and PNNP tetradentate ligands (WO02/40155 A1) in the catalytic hydrogenation of C═O and C═Ncarbon-heteroatom double bonds for the production of alcohols andamines, respectively. Noyori and coworkers have also described anefficient catalyst system generated from the complexRu(η⁶-arene)(tosyldiamine)Cl for the asymmetric hydrogenation of iminesby transferring hydrogen from triethylammonium formate (Noyori et al.,Acc. Chem. Res. 1997, 30, 97-102).

Noyori and co-workers have pioneered the use of ruthenium complexesbearing a chelating diphosphine ligand (or two monodentate phosphines)and a chelating diamine ligand for the catalytic asymmetrichydrogenation of ketones. At least one and usually both of the chelatingligands are chiral. The various papers and patents of Noyori et al. havedemonstrated the highly efficient reduction of various functionalisedand unfunctionalised ketones using this class of catalysts. It was alsodemonstrated by Noyori and co-workers (Ohkuma et al., J. Am. Chem. Soc.,1995, 107, 2675 and 10417) that a fully isolated and characterisedruthenium(II)diphosphinediamine complex could be used as catalyst. Highactivity and high selectivity were generally associated with the use ofchiral biaryl-phosphines (eg. Tol-BINAP and Xyl-BINAP) and diamines (eg.DPEN and DAIPEN) as ligands.

It has been reported that similar classes of Noyori-typeruthenium(II)(phosphine)₂(diamine) complexes could catalyse thehydrogenation and asymmetric hydrogenation of activated (aromatic)imines (Abdur-Rashid et al., Organometallics, 2000, 20, 1655) orruthenium(II)diphosphinediamine complexes (Abdur-Rashid et al.,Presentations at The Canadian Society for Chemistry 83^(rd) Conferenceand Exhibition, Calgary, Alberta, May 2000, and subsequentlyAbdur-Rashid et al., Organometallics, 2001, 21, 1047). Since thesepublications, Chirotech Technology Limited has also reported similarimine hydrogenation processes (Cobley et al. WO 02/08169 A1; Cobley atal. Adv. Synth. Catal. 2003, 345, 195) based on similar classes ofcomplexes and imine substrates. It is noted that the reports ofAbdur-Rashid et al. and Chirotech Technology Limited both relate to theuse of Noyori-type ruthenium(II)-(phosphine)₂(diamine) andruthenium(II)diphosphinediamine complexes as catalysts for the reductionof activated imines of the Formula A shown below in which R representsan activating aryl group, R′ represents an alkyl group and R″ representseither an aryl or benzyl group.

In yet another publication (Abdur-Rashid et al., PCT/CA03/00689), theuse of other similar Noyori-type ruthenium(II) complexes for thehydrogenation and asymmetric hydrogenation of unactivated imines hasbeen reported, in which R and R′ in the Formula A simultaneously orindependently represent alkyl or alkenyl substituents and R″ representseither an aryl, alkyl or alkenyl substituent. The imines described inthis latter publication are inherently more difficult to reduce than theactivated (aromatic) analogues reported by Chirotech.

To date, there are no reports in the literature which teach the use ofsuch Noyori-type catalysts in hydrogenation processes for the reductionof a class of imines in which, in Formula A, R represents aryl; R′represents cyclic, alkyl, alkenyl, alkynyl or aryl; and R″ representscyclic or acyclic alkyl.

There is also a continuing demand for an enantioselective iminehydrogenation procedure that allows for the facile preparation of chiralprimary amines in high yields and stereoselectivities. Such chiralprimary amines are desired as valuable precursors, intermediates and endproducts in the pharmaceutical, agrochemical, fine chemical and materialindustries.

SUMMARY OF TIHE INVENTION

It has now been found that hydrogenation of the carbon-nitrogen doublebond (C═N) of imines of Formula (I) to the corresponding amines ofFormula (II) can be efficiently carried out using a catalytic systemincluding a ruthenium complex containing (1) a diamine and (2) adiphosphine or two monodentate phosphine ligands.

Therefore, the present invention includes a process for thehydrogenation of the carbon-nitrogen double bond (C═N) of imines ofFormula (I) to the corresponding amines of Formula (II) comprisingcontacting the imines of Formula (I) with molecular hydrogen (H₂) and acatalytic system including a ruthenium complex containing (1) a diamineand (2) a diphosphine or two monodentate phosphine ligands. Suchprocesses also relate to the asymmetric hydrogenation of prochiralimines to the chiral amines using chiral ruthenium complexes bearingchiral diphosphines or chiral monodentate phosphines and chiraldiamines.

Accordingly, the present invention relates to a process for thehydrogenation and/or asymmetric hydrogenation of an imine of Formula (I)to an amine of Formula (II):

whereinR¹ is selected from the group consisting of aryl and heteroaryl, whichtwo groups are optionally substituted;R² is selected from the group consisting of hydrogen, aryl, heteroaryl,C₁₋₁₀alkyl C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkenyl and C₃₋₁₀heterocyclo, which latter eight groups areoptionally substituted; andR³ is selected from the group consisting of optionally substituted C₁ toC₂ alkyl and optionally substituted C₃₋₁₀cycloalkyl;or R¹ and R² or R² and R³ are linked to form an optionally substitutedring;wherein the optional substituents of R¹ and R² are independentlyselected from one or more of the group consisting of halo, NO₂, OR⁴, NR⁴₂ and R⁴, in which R⁴ is independently selected from one or more of thegroup consisting of hydrogen, aryl, C₁₋₆alkyl C₂₋₆alkenyl,C₁₋₆cycloalkyl and C₁₋₆cycloalkenyl;the optional substituents of R³ are independently selected from one ormore of the group consisting of halo, NO₂, OR⁵, NR⁵ ₂ and R⁵, in whichR⁵ is independently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; andone or more of the carbon atoms in the alkyl alkenyl and/or alkynylgroups of R¹, R² and/or R³ is optionally replaced with a heteroatomselected from the group consisting of O, S, N, P and Si, which, wherepossible, is optionally substituted with one or more C₁₋₆alkyl groups,said process comprising the steps of reacting imines of Formula (I) inthe presence of H₂, a base and a catalytic system in which the catalyticsystem includes a base and a ruthenium complex comprising (1) a diamineand (2) a diphosphine ligand or monodentate phosphine ligands.

In an embodiment, the present invention also relates to a process forthe hydrogenation and/or asymmetric hydrogenation of an imine of Formula(III) to an amine of Formula (IV):

whereinR⁴ and R⁵ represent simultaneously or independently any substituent,including but not limited to hydrogen, aryl, heteroaryl, C₁₋₁₀alkylC₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl andC₃₋₁₀heterocyclo, which latter eight groups are optionally substituted,orR⁴ and R⁵ are linked together to form an optionally substituted ring;R⁶ is selected from the group consisting of H, aryl, C ₁₋₁₀alkylC₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl and C₃₋₁₀cycloalkenyl, whichlatter six groups are optionally substituted;wherein the optional substituents of R⁴, R⁵ and R⁶ are independentlyselected from one or more of the group consisting of halo, NO₂, OR⁷, NR⁷₂ and R⁷, in which R⁷ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl; andone or more of the carbon atoms in the alkyl, alkenyl and/or alkynylgroups of R⁴, R⁵ and/or R⁶ are optionally replaced with a heteroatomselected from the group consisting of O, S, N, P and Si, which, wherepossible, is optionally substituted with one or more C₁₋₆alkyl groups,said process comprising the steps of reacting imines of Formula (III) inthe presence of H₂, a base and a catalytic system in which the catalyticsystem includes a base and a ruthenium complex comprising (1) a diamineand (2) a diphosphine ligand or monodentate phosphine ligands.

The present invention also relates to a very effective process for thepreparation of primary amines of Formula V, by selectively removing thepropargyl group from the secondary amine of the Formula IV.

The processes of the invention may, in particular be applied to thepreparation of enantiomerically enriched chiral amines of Formulae (II),(IV) and (V), or the opposite enantiomers thereof.

In embodiments of the invention, the ruthenium complex has the generalFormula RuXY(PR₃)₂(NH₂—Z—NH₂) (VI) or RuXY(R₂P—Q—PR₂)(NH₂—Z—NH₂) (VII),where Z and Q represent a chiral or achiral linker; the ancilliaryligands PR₃ and R₂P—Q—PR₂ represent monodentate and bidertatephosphines, respectively; and the ligands X and Y represent an anionicligand.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

In one of its embodiments, the present invention relates to a processfor the hydrogenation and/or asymmetric hydrogenation of an imine ofFormula (I) to an amine of Formula (II) and/or its other enantiomer:

whereinR¹ is selected from the group consisting of aryl and heteroaryl whichtwo groups are optionally substituted;R² is selected from the group consisting of hydrogen, aryl, heteroaryl,C₁₋₁₀alkyl C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl,C₃₋₁₀cycloalkenyl and C₃₋₁₀heterocyclo, which latter eight groups areoptionally substituted; andR³ is selected from the group consisting of optionally substituted C₁ toC₂ alkyl and optionally substituted C₃₋₁₀cycloalkyl;or R¹ and R² or R² and R³ are linked to form an optionally substitutedring;wherein the optional substituents of R¹ and R² are independentlyselected from one or more of the group consisting of halo, NO₂, OR⁴, NR⁴₂ and R⁴, in which R⁴ is independently selected from one or more of thegroup consisting of hydrogen, aryl, C₁₋₆alkyl C₂₋₆alkenyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkenyl;the optional substituents of R³ are independently selected from one ormore of the group consisting of halo, NO₂, OR⁵, NR⁵ ₂ and R⁵, in whichR⁵ is independently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl; andone or more of the carbon atoms in the alkyl alkenyl and/or alkynylgroups of R¹, R² and/or R³ is optionally replaced with a heteroatomselected from the group consisting of O, S, N, P and Si, which, wherepossible, is optionally substituted with one or more C₁₋₆alkyl groups,said process comprising the steps of reacting imines of Formula (I) inthe presence of H₂, and a catalytic system in which the catalytic systemincludes a base and a ruthenium complex comprising (1) a diamine and (2)a diphosphine ligand or monodentate phosphine ligands.

In another embodiment, the present invention also relates to a processfor the hydrogenation and/or asymmetric hydrogenation of an imine ofFormula (III) to an amine of Formula (IV):

whereinR⁴ and R⁵ represent simultaneously or independently any substituent,including but not limited to hydrogen, aryl, heteroaryl, C₁₋₁₀alkylC₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl andC₃₋₁₀heterocyclo, which latter eight groups are optionally substituted,orR⁴ and R⁵ are linked together to form an optionally substituted ring;R⁶ is selected from the group consisting of H, aryl, C ₁₋₁₀alkylC₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl and C₃₋₁₀cycloalkenyl, whichlatter six groups are optionally substituted;wherein the optional substituents of R⁴, R⁵ and R⁶ are independentlyselected from one or more of the group consisting of halo, NO₂, OR⁷, NR⁷₂ and R⁷, in which R⁷ is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl; andone or more of the carbon atoms in the alkyl, alkenyl and/or alkynylgroups of R⁴, R⁵ and/or R⁶ are optionally replaced with a heteroatomselected from the group consisting of O, S, N, P and Si, which, wherepossible, is optionally substituted with one or more C₁₋₆alkyl groups,said process comprising the steps of reacting imines of Formula (III) inthe presence of H₂, and a catalytic system in which the catalytic systemincludes a base and a ruthenium complex comprising (1) a diamine and (2)a diphosphine ligand or monodentate phosphine ligands.

The present invention also relates to a very effective process for thepreparation of primary amines of Formula V, by selectively removing thepropargyl group from the secondary amine of the Formula IV.

The processes of the invention may, in particular be applied to thepreparation of enantiomerically enriched chiral amines of Formulae (II),(IV) and (V), or the opposite enantiomers thereof. Suitably, theprocesses of the present invention provide an effective means ofpreparing a wide range of chiral amines. It is desirable that theenantiomeric enrichment of the amines (II) and (IV) is at least 50% ee,and more suitably at least 80% ee, or higher. If necessary, anyshortfall in ee can be subsequently corrected by crystallizationtechniques known by persons skilled in the art. It is also desirable toachieve a high conversion of substrate to product, suitably at least 80%conversion, and more suitably at least 90% conversion.

The term “aryl” as used herein means an unsaturated aromatic carbocyclicgroup containing from six to fourteen carbon atoms having a single ring(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl oranthryl). In an embodiment of the invention, aryl includes phenyl andnaphthyl, in particular phenyl.

The term “heteroaryl” as used herein means an unsaturated aromaticcarbocyclic group containing from five to fourteen carbon atoms having asingle ring or multiple condensed (fused) and wherein one or more,suitably one or three, more suitably one to two, even more suitably oneof the carbon atoms in the aromatic group is replaced with a heteroatomselected from the group consisting of O, S, and N which, where possible,is optionally substituted with one or more alkyl groups. Examples ofsuitable heteroaryl groups include, but are not limited to, pyridyl,thieryl, furanyl, pyrrolyl, and their corresponding benzo-fused ringsystems (for example indolyl and benzofuranyl) and the like.

The term “alkyl” as used herein means a saturated, linear or branchedalkyl group containing the specified number of carbon atoms.

The term “cycloalkyl” as used herein means a saturated carbocyclic groupcontaining the specified number of carbon atoms and having a single ring(e.g., cyclohexyl and cyclopentyl) or multiple condensed (fused) rings(e.g decahydronaphthalene and adamantanyl).

The term “alkenyl” as used herein means an unsaturated, linear orbranched alkenyl group containing the specified number of carbon atomsand includes vinyl, allyl, butenyl and the like. The alkenyl groups maycontain any number of double bonds. Suitably, the alkenyl group containsone double bond.

The term “cycloalkenyl” as used herein means a unsaturated carbocyclicgroup containing the specified number of carbon atoms and having asingle ring (e.g., cyclohexenyl and cyclopentenyl) or multiple condensed(fused) rings (e.g octahydronaphthalene). The cycloalkenyl groups maycontain any number of double bonds. Suitably, the cycloalkenyl groupcontains one double bond

The term “alkynyl” as used herein means an unsaturated, linear orbranched alkynyl group containing the specified number of carbon atomsand includes ethynyl, propynyl, propargyl, butynyl and the like. Thealkynyl groups may contain any number of triple bonds. Suitably, thealkynyl group contains one triple bond.

The term “halo” as used herein means halogen and includes chloro, bromo,iodo, fluoro and the like.

When R¹ and R² are linked together, or with R³, or when R⁵ and R⁶ arelinked together to form one or more carbocyclic rings, said rings maycontain from three to twelve atoms, suitably three to ten atoms, havinga single ring structure or multiple condensed (fused) ring structure.Further in the rings, one or more, suitably one or two, more suitablyone, of the carbon atoms may be substituted with a heteroatom selectedfrom O, S, N, P and Si, which where possible, is optionally substitutedwith one or more C₁₋₆alkyl groups. Suitably, one or more, more suitablyone or two, even more suitably one, of the carbon atoms of the ring maybe substituted with a heteroatom selected from O, S, N, NH and N—CH₃.

In the compounds of Formula I, R¹ is selected from the group consistingof aryl and heteroaryl, which two groups are optionally substituted. Inembodiments of the invention R¹ is optionally substituted aryl, suitablyoptionally substituted phenyl, more suitably unsubstituted phenyl.

Further, in the compounds of Formula I, R² is selected from the groupconsisting of hydrogen, aryl, heteroaryl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀cycloakyl, C₃₋₁₀cycloalkenyl and C₃₋₁₀heterocyclo,which latter eight groups are optionally substituted. In embodiments ofthe invention R² is selected from the group consisting of hydrogen,aryl, C₁₋₆alky C₂₋₆alkenyl, C₂₋₆alknyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkenyl, which latter six groups are optionally substituted. Infurther embodiments of the invention, R² is selected from the groupconsisting of hydrogen, aryl and C₁₋₆alkyl, which latter two groups areoptionally substituted. In still further embodiments of the invention R²is selected from the group consisting of hydrogen, phenyl, andC₁₋₆alkyl, which latter two groups are optionally substituted. In stillfurther embodiments of the invention R² is selected from the groupconsisting of hydrogen, unsubstituted phenyl and methyl.

Still further, in the compounds of Formula I, R³ is selected from thegroup consisting of optionally substituted C₁ to C₂ alkyl and optionallysubstituted C₃₋₁₀cycloalkyl. In embodiments of the invention, R³ isselected from the group consisting of optionally substituted C₁ to C₂alkyl and optionally substituted C₃₋₆cycloalkyl. In a further embodimentof the invention, R³ is methyl, ethyl i-propyl (ethyl substituted withmethyl), cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, whichlatter four groups are unsubstituted.

The invention also extends to compounds of Formula I wherein R₁ and R²or R² and R³ are linked to form an optionally substituted ring. Inembodiments of the invention R² and R³ (including the atoms to whichthey are attached) are linked to form an optionally substituted,suitably unsubstituted, 5- or 6-membered ring, with the linking groupbeing a C₃ to C₄ alkylene group.

As stated above, the optional substituents for R¹ and R² in thecompounds of Formula I, are independently selected from one or more ofthe group consisting of halo, NO₂, OR⁴, NR⁴ ₂ and R⁴, in which R⁴ isindependently selected from one or more of the group consisting ofhydrogen, aryl, C₁₋₆alkyl C₂₋₆alkenyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkenyl, and the optional substituents of R³ are independentlyselected from one or more of the group consisting of halo, NO₂, OR⁵, NR⁵₂ and R⁵, in which R⁵ is independently selected from the groupconsisting of C₁₋₆alkyl C₂₋₆alkenyl and C₂₋₆alkynyl. In embodiments ofthe invention, the optional substituents for R¹ and R² in the compoundsof Formula I, are independently selected from one or more of the groupconsisting of halo, NO₂, OR⁴, NR⁴ ₂ and R⁴, in which R⁴ is independentlyselected from one or more of the group consisting of hydrogen, aryl andC₁₋₄alkyl and the optional substituents of R³ are independently selectedfrom one or more of the group consisting of halo, NO₂, OR⁵, NR⁵ ₂ andR⁵, in which R⁵ is independently selected from the group consisting ofC₁₋₄allyl. In further embodiments of the invention, the optionalsubstituents for R¹ and R² in the compounds of Formula I, areindependently selected from one or more of the group consisting of halo,NO₂, OH, OCH₃, NH₂, N(CH₃)₂, CH₃ and phenyl, and the optionalsubstituents of R³ are independently selected from one or more of thegroup consisting of halo, NO₂, OH, OCH₃, NH₂, N(CH₃)₂ and CH₃.

The compounds of Formula I also include those in which one or more ofthe carbon atoms in the alkyl, alkenyl and/or alkynyl groups of R¹, R²and/or R³ is optionally replaced with a heteroatom selected from thegroup consisting of O, S, N, P and Si, which, where possible, isoptionally substituted with one or more C₁₋₆alkyl groups. In anembodiment of the invention, one to three, suitably one or two, moresuitably one, of the carbon atoms in the alkyl alkenyl and/or alkynylgroups of R¹, R² and/or R³ is optionally replaced with a heteroatomselected from the group consisting of O, S, N, NH and N—CH₃.

In the compounds of Formula III, R⁴ and R⁵ represent simultaneously orindependently any substituent, including but not limited to hydrogen,aryl, heteroaryl C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl or C₃₋₁₀heterocyclo, which lattereight groups are optionally substituted. In embodiments of theinvention, R⁴ and R⁵ represent simultaneously or independently hydrogen,aryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl orC₃₋₆cycloalkenyl, which latter six groups are optionally substituted. Infurther embodiments of the invention, R⁴ and R⁵ represent simulaneouslyor independently hydrogen, aryl or C₁₋₆alkyl, which latter two groupsare optionally substituted. In still further embodiments of theinvention R⁴ and R⁵ represent simulaneously or independently hydrogen,phenyl, and C₁₋₆alkyl, which latter two groups are optionallysubstituted. In still further embodiments of the invention R⁴ and R⁵represent simultaneously or independently hydrogen, unsubstituted phenylor methyl.

Further, in compounds of Formula III, R⁴ and R⁵ may be linked togetherto form an optionally substituted ring. In embodiments of the inventionR⁴ and R⁵ (including the atoms to which they are attached) are linked toform an optionally substituted, suitably unsubstituted, 5- or 6-memberedring, with the linking group being a C₃ to C₄ alkylene group.

The present invention also involves the use of compounds of Formula IIIin which R⁶ is selected from the group consisting of H, aryl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl andC₃₋₁₀cycloalkenyl, which latter six groups are optionally substituted.In embodiments of the invention, R⁶ is selected from the groupconsisting of H, aryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl and C₃₋₆cycloalkenyl, which latter six groups areoptionally substituted. In still further embodiments of the invention,R⁶ is selected from the group consisting of H and C₁₋₄alkyl, suitably H.

As stated above, the optional substituents for R⁴, R⁵ and R⁶ in thecompounds of Formula III, are independently selected from one or more ofthe group consisting of halo, NO₂, OR⁷, NR⁷ ₂ and R⁷, in which R⁷ isindependently selected from the group consisting of C₁₋₆alkyl,C₂₋₆alkenyl and C₂₋₆alkynyl. In embodiments of the invention, theoptional substituents for R⁴, R⁵ and R⁶ in the compounds of Formula III,are independently selected from one or more of the group consisting ofhalo, NO₂, OR⁷, NR⁷ ₂ and R⁷, in which R⁷ is independently selected fromone or more of the group consisting of C₁₋₄alkyl. In further embodimentsof the invention, the optional substituents for R⁴, R⁵ and R⁶ in thecompounds of Formula III, are independently selected from one or more ofthe group consisting of halo, NO₂, OH, OCH₃, NH₂, N(CH₃)₂ and CH₃,

The compounds of Formula III also include those in which one or more ofthe carbon atoms in the alkyl, alkenyl and/or alkynyl groups of R⁴, R⁵and/or R⁶ is optionally replaced with a heteroatom selected from thegroup consisting of O, S, N, P and Si, which, where possible, isoptionally substituted with one or more C₁₋₆alkyl groups. In anembodiment of the invention, one to three, suitably one or two, moresuitably one, of the carbon atoms in the alkyl alkenyl and/or alkynylgroups of R⁴, R⁵ and/or R⁶ is optionally replaced with a heteroatomselected from the group consisting of O, S, N, NH and N—CH₃.

As to any of the above groups in the compounds of Formulae I-IV, thatcontain one or more substituents, it is understood, of course, that suchgroups do not contain any substitution or substitution patterns whichare sterically impractical and/or synthetically non-feasible.

The present invention also relates to a very effective process for thepreparation of primary amines of Formula V, wherein R⁴and R⁵ are asdefined in Formula IV, by selectively removing the propargyl group fromthe secondary amine of the Formula IV.

The propargyl group can be removed using any suitable method, forexample using TiCl₃ and lithium according to the procedure of Banerji etal. (Tetrahedron Lett. 1999, 40, 767-770).

The process of the invention involves the catalytic hydrogenation orasymmetric hydrogenation of an imine of the Formula I or III, in thepresence of a base and an achiral or chiral ruthenium complex containinga diamine ligand of the general Formula RuXY(PR₃)₂(NH₂—Z—NH₂) (VI) orRuXY(R₂P—Q—PR₂)(NH₂—Z—NH₂) (VII), where Z and Q represent a chiral orachiral linker; the anciliary ligands PR₃ and R₂P—Q—PR₂ representmonodentate and bidentate phosphines, respectively; and the ligands Xand Y represent an anionic ligand. More particularly, the ligands X andY are selected from the group consisting of Cl, Br, I, H, hydroxy,alkoxy and acyloxy.

In embodiments of the invention, the ligand PR₃:

represents a chiral or achiral monodentate phosphine ligand in which Ris simultaneously or independently selected from the group consisting ofoptionally substituted linear and branched allyl containing 1 to 8carbon atoms, optionally substituted linear and branched alkenylcontaining 2 to 8 carbon atoms, optionally substituted cycloalkyl,optionally substituted aryl, OR and NR₂; or two R groups bonded to thesame P atom are bonded together to form a ring having 5 to 8 atoms andincluding the phosphorous atom to which said R groups are bonded.

In embodiments of the present invention, the ligand R₂P—Q—PR₂:

represents a bidentate ligand in which R is simultaneously orindependently selected from the group consisting of optionallysubstituted linear and branched alkyl containing 1 to 8 carbon atoms,optionally substituted linear and branched alkenyl containing 2 to 8carbon atoms, optionally substituted cycloalkyl, optionally substitutedaryl, OR and NR₂; or two R groups bonded to the same P atom are bondedtogether to form a ring having 5 to 8 atoms and including thephosphorous atom to which said R groups are bonded; and Q is selectedfrom the group consisting of linear and cyclic C₂-C₇ alkylene,optionally substituted metallocenediyl and optionally substituted C₆-C₂₂arylene.

In further embodiments of the invention, the ligand R₂P—Q—PR₂ is chiraland includes atropisomeric bis-tertiary phosphines, in which the twophosphorus atoms are linked by a biaryl backbone. More particularly, theligand R₂P—Q—PR₂ is selected from the group consisting of BINAP, BIPHEPand BIPHEMP:

In embodiments of the invention, the bidentate phosphine is a chiral orachiral ligand of the type R₂P—NR⁵—Z—NR⁵—PR₂:

wherein each R, taken separately, is independently selected from thegroup consisting of optionally substituted linear and branched alkylgroup containing 1 to 8 carbon atoms, optionally substituted linear andbranched alkenyl group containing 2 to 8 carbon atoms, optionallysubstituted cycloalkyl, optionally substituted aryl, OR and NR₂; or twoR groups bonded to the same P atom are bonded together to form a ringhaving 5 to 8 atoms and including the phosphorous atom to which said Rgroups are bonded; each R⁸, is independently selected from the groupconsisting of hydrogen, optionally substituted linear and branched alkylgroup containing 1 to 8 carbon atoms, optionally substituted linear andbranched alkenyl group containing 2 to 8 carbon atoms, optionallysubstituted cycloalkyl, optionally substituted aryl, OR and NR₂; and Zis optionally substituted linear and cyclic C₂-C₇ alkylene, optionallysubstituted metallocenediyl and optionally substituted C₆-C₂₂ arylene.More particularly, the ligand R₂P—NR⁵—Z—NR⁵—PR₂ (V) is selected from thegroup consisting of DPPACH and DCYPPACH:

The present invention also includes within its scope the process inwhich the diamine ligand has the Formula NH₂—Z—NH₂:

wherein Z is selected from the group consisting of optionallysubstituted linear and cyclic C₂-C₇ alkylene, optionally substitutedmetallocenediyl and optionally substituted C₆-C₂₂ arylene. In furtherembodiments of the invention, the diamine ligand is chiral and includes(1) compounds in which at least one of the amine-bearing centers isstereogenic, (2) compounds in which both of the amine-bearing centersare stereogenic and (3) atropisomeric bis-tertiary diamines, in whichthe two nitrogen atoms are linked by a biaryl backbone. Still further,the diamine ligand NH₂—Z—NH₂ is selected from the group consisting ofCYDN and DPEN:

In embodiments of the invention, the diamine is a bidentate ligand ofthe Formula D—Z—NHR⁹ in which Z is selected from the group consisting ofoptionally substituted linear and cyclic C₂-C₇ alkylene, optionallysubstituted metallocenediyl and optionally substituted C₆-C₂₂ arylene; Dis an amido group donor or a chalcogenide radical selected from thegroup consisting of O, S, Se and Te; NHR⁹ is an amino group donor inwhich R⁹ is selected from the group consisting of hydrogen, optionallysubstituted linear and branched alkyl group containing 1 to 8 carbonatoms, optionally substituted linear and branched alkenyl groupcontaining 2 to 8 carbon atoms, optionally substituted cycloalkyl andoptionally substituted aryl. In more particular embodiments of theinvention, D is NR¹⁰, in which R¹⁰ is selected from the group consistingof S(O)₂R¹¹, P(O)(R¹¹)₂, C(O)R¹¹, C(O)N(R¹¹)₂ and C(S)N(R¹¹)₂, in whichR¹¹ is independently selected from the group consisting of hydrogen,optionally substituted linear and branched alkyl group containing 1 to 8carbon atoms, optionally substituted linear and branched alkenyl groupcontaining 2 to 8 carbon atoms, optionally substituted cycloalkyl andoptionally substituted aryl. In embodiments of the invention, thediamine is chiral and includes (1) compounds in which the amine-bearingcenter is stereogenic, (2) compounds in which both the donor-bearing (D)and amine-bearing centers are stereogenic. More particularly, thediamine is CH₃C₆H₄SO₃NCHPhCHPhNH₂.

The term “metallocenediyl” as used herein refers to a bivalentmetallocene group, typically having one of the following structures:

in which M is a metal, for example iron (Fe).

The term “arylene” as used herein includes biaryldiyl groups and refersto a bivalent group comprising one to three, suitably one to two, arylgroups linked together. Examples of arylene groups include, but are notlimited to biphenyldiyl and binaphthyldiyl.

The term “optionally substituted” as used herein in the various ligandsfor the ruthenium complexes means that the corresponding group is eitherunsubstituted or substituted. When a group is substituted thesubstituents may include one to five, sutiably one to three, moresuitably one to two, groups selected from but not limited to alkyl,alkoxy, polyalkyleneglycol, carboxylic esters, OH, halo, cycloalkyl,aryl, and halo-substituted-aryl. As to any of the above groups thatcontain one or more substituents, it is understood, of course, that suchgroups do not contain any substitution or substitution patterns whichare sterically impractical and/or synthetically non-feasible.

The term “halo” as used herein means halogen and includes chloro,fluoro, bromo and iodo.

The term “alkoxy” as used herein means saturated, cyclic, linear orbranched O-alkyl groups containing from one to ten, suitably one toeight, more suitably one to six carbon atoms and includes methoxy,ethoxy, propoxy, t-butoxy and the like.

The term “acyloxy” as used herein means saturated, cyclic, linear orbranched O-acyl groups containing from one to ten, suitably one toeight, more suitably one to six carbon atoms and includes acetoxy andthe like.

The ruthenium catalyst complexes may be prepared, for example, asdescribed by Abdur-Rashid et al. (Organometallics, 2001, 21, 1047). Manyof the ligands described above are known in the art and, unlessspecified otherwise in the Examples, are obtained according to methodsknown in the art. The ligands that are new can be obtained by modifyingknown procedures according to the knowledge of a person skilled in theart.

As previously mentioned, the catalytic system characterizing the processof the present invention comprises a base. Said base can be thesubstrate itself, if the latter is basic, or any conventional base. Onecan cite, as non-limiting examples, organic non-coordinating bases suchas DBU, tertiary organic amines, phosphazene bases, an alkaline oralkaline-earth metal carbonate, a carboxylate salt such as sodium orpotassium acetate, or an alcoholate or hydroxide salt. Suitable basesare the alcoholate or hydroxide salts selected from the group consistingof the compounds of Formula (R¹²O)₂M′ and R¹²OM″, wherein M′ is analkaline-earth metal, M″ is an alkaline metal and R¹² stands forhydrogen or a C₁ to C₆ linear or branched alkyl radical. Also within thescope of the present invention, the base may be an organicnon-coordinating base.

A typical process implies the mixture of the substrate with theruthenium complex and a base, possibly in the presence of a solvent, andthen treating such a mixture with molecular hydrogen at a chosenpressure and temperature.

The complexes can be added to the reaction medium in a large range ofconcentrations. As non-limiting examples, one can cite substrate tocomplex (S/com) ratio of 20 to 10⁵. Preferably, the substrate to complexratio will be in the range of 1000 to 10⁴, respectively. It goes withoutsaying that the optimum concentration of complex will depend on thenature of the latter and on the pressure of H₂ used during the process.

Useful quantities of base, added to the reaction mixture, may becomprised in a relatively large range. One can cite, as non-limitingexamples, ranges between 1 to 50000 molar equivalents relative to thecomplex, preferably 10 to 2000. However, it should be noted that it isalso possible to add a small amount of base (e.g. base/com=1 to 3) toachieve high hydrogenation yields.

The hydrogenation reaction can be carried out in the presence or absenceof a solvent. When a solvent is required or used for practical reasons,then any solvent current in hydrogenation reactions can be used for thepurposes of the invention. Non-limiting examples include aromaticsolvents such as benzene, toluene or xylene, hydrocarbon solvents suchas hexane or cyclohexane, ethers such as tetrahydrofuran, or yet primaryor secondary alcohols, or mixtures thereof. Still further, the solventmay be an amine solvent. A person skilled in the art is well able toselect the solvent most convenient in each case to optimize thehydrogenation reaction.

In the hydrogenation process of the invention, the reaction can becarried out at a H₂ pressure comprised between 10⁵ Pa and 80×10⁵ Pa (1to 80 bars). Again, a person skilled in the art is well able to adjustthe pressure as a function of the catalyst load and of the dilution ofthe substrate in the solvent. As examples, one can cite typicalpressures of 1 to 40×10⁵ Pa (1 to 40 bar).

The temperature at which the hydrogenation can be carried out iscomprised between 0° C. and 100° C., more preferably in the range ofbetween 20° C. and 60° C. Of course, a person skilled in the art is alsoable to select the preferred temperature as a function of the meltingand boiling point of the starting and final products.

The following non-limiting examples are illustrative of the presentinvention:

EXAMPLES

Materials and Methods

The invention will now be described in further details by way of thefollowing examples, wherein the temperatures are indicated in degreescentigrade and the abbreviations have the usual meaning in the art. Theligand R,R-DPPACH is a known compound that was previously used inrhodium complexes for the hydrogenation of C═C double bonds (Fioriani etal., J. Mol. Catal., 1979, 5, 303), (Onuma et al., Bull. Chem. Soc.Jpn., 1980, 53, 2012; Chem. Lett., 1980, 5, 481).

All the procedures described hereafter have been carried out under aninert atmosphere unless stated otherwise. Hydrogenations were carriedout in open glass tubes placed inside a stainless steel autoclave orSchlenk flasks attached to a vacuum line. Hydrogen gas was used asreceived. All preparations and manipulations were carried out under H₂,N₂ or Ar atmospheres with the use of standard Schlenk, vacuum line andglove box techniques in dry, oxygen-free solvents. Tetrahydrofuran(THF), diethyl ether (Et₂O) and hexanes were dried and distilled fromsodium benzophenone ketyl. Deuterated solvents were degassed and driedover activated molecular sieves. Ruthenium trichloride,triphenylphosphine, RR-DPEN, R,R-CYDN, ketones and amines were purchasedfrom Aldrich. Imines were prepared using previously reported procedures(Organometallics 2001, 21, 1047; J. Am. Chem. Soc 1996, 118, 6784; J.Am. Chem. Soc 1994, 116, 8952; J. Org. Chem. Soc 1993, 58, 7627).Selective removal of the N-propargyl protecting group from aminesfollowed the procedure which was previously reported by Banerji et al.(Tetrahedron Lett. 1999, 40, 767). The precursor complex RuHCl(PPh₃)₃was prepared by a modification of the procedure reported by Schunn etal. (Inorg. Synth. 1970, 131). The complexes RuHCl(R-BINAP)(PPh₃),RuHCl(R,R-DPPACH)(PPh₃), RuHCl(R-BINAP)(RR-CYDN), RuHCl(R-BINAP)(R,R-DPEN), RuHCl(RR-DPPACH)(R,R-CYDN) and RuHCl(RR-DPPACH) (R,R-DPEN)were prepared as described in Organometallics, 2001, 21, 1047. NMRspectra were recorded on either a Varian Gemini 300 MHz spectrometer(300 MHz for ¹H, 75 MHz for ¹³C and 121.5 for ³¹P) or a Varian Unity 400MHz spectrometer (400 MHz for ¹H and 100 MHz for ¹³C). All ³¹P spectrawere recorded with proton decoupling and ³¹P chemical shifts weremeasured relative to 85% H₃PO₄ as an external reference. ¹H and ¹³Cchemical shifts were measured relative to partially deuterated solventpeaks but are reported relative to tetramethylsilane.Structure of the Ligands Used in the Examples are Shown Below:

Example 1 General Procedure for Catalytic Hydrogenation

A solution of the required imine dissolved in benzene was added to amixture of the catalyst (0.1-0.5%) and KO^(t)Bu (10-50 mg) in a 50 mlParr hydrogenation reactor (fitted with a removable glass liner and amagnetic stirring bar). The reactor was then purged several times withH₂ gas, pressurized to the desired pressure (10-50 bar) and stirredvigorously at the required temperature. The pressure was periodicallyreleased and the hydrogenation reaction monitored by removing a sampleof the reaction mixture and measuring its ¹H NMR spectrum. If required,the mixture was re-pressurized with H₂ gas and the reaction continueduntil either the hydrogenation is complete or no further change in thecomposition was observed (NMR). Upon completion, hexane (10 ml) wasadded to the reaction mixture, which was then eluted (hexane) through ashort column of silica gel in order to remove the spent catalyst andKO^(t)Bu. Evaporation of the hexane under reduced pressure yielded theproduct.

Results of the Catalytic hydrogenation using the series ofRuHCl(diphosphine)(diamine) complexes are summarized below.

Example 1.1 Hydrogenation of N-(Benzylidene)methylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 1000 100 24RuHCl(R-BINAP)(R,R-DPEN) 1000 100 24 RuHCl(R,R-DPPACH)(R,R-CYDN) 1000100 24 RuHCl(R,R-DPPACH)(R,R-DPEN) 1000 100 24

Example 1.2 Hydrogenation of N-(1-Phenylethylidene)methylamine

Conv. Catalyst S:C (%) Time/hr ee(%)* RuHCl(R-BINAP)(R,R-CYDN) 600 98 2462 (S) RuHCl(R-BINAP)(R,R-DPEN) 600 97 24 71 (S)RuHCl(R,R-DPPACH)(R,R-CYDN) 600 100 24 48 (S)RuHCl(R,R-DPPACH)(R,R-DPEN) 600 100 24 51 (S)*The ee was determined from the rotation (α_(D)) ofN-methyl-1-phenylethylamine.

Example 1.3 Hydrogenation of N-(Benzylhydrylidene)methylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 500 100 24RuHCl(R-BINAP)(R,R-DPEN) 500 100 24 RuHCl(R,R-DPPACH)(R,R-CYDN) 500 10024 RuHCl(R,R-DPPACH)(R,R-DPEN) 500 100 24

Example 1.4 Hydrogenation of N-(Benzylidene)ethylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 1000 100 24RuHCl(R-BINAP)(R,R-DPEN) 1000 100 24 RuHCl(R,R-DPPACH)(R,R-CYDN) 1000100 24 RuHCl(R,R-DPPACH)(R,R-DPEN) 1000 100 24

Example 1.5 Hydrogenation of N-(1-Phenylethylidene)ethylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 500 95 36RuHCl(R-BINAP)(R,R-DPEN) 500 98 36 RuHCl(R,R-DPPACH)(R,R-CYDN) 500 10024 RuHCl(R,R-DPPACH)(R,R-DPEN) 500 100 24

Example 1.6 Hydrogenation of N-(1-Phenylethylidene)-2-propylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 500 75 36RuHCl(R-BINAP)(R,R-DPEN) 500 72 36 RuHCl(R,R-DPPACH)(R,R-CYDN) 500 87 24RuHCl(R,R-DPPACH)(R,R-DPEN) 500 91 24

Example 1.7 Hydrogenation of N-(1-Phenylethylidene)cyclopentylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 200 91 36RuHCl(R-BINAP)(R,R-DPEN) 200 83 36 RuHCl(R,R-DPPACH)(R,R-CYDN) 200 97 36RuHCl(R,R-DPPACH)(R,R-DPEN) 200 95 36

Example 1.8 Hydrogenation of 2-phenyl-1-pyrroline

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 200 92 36RuHCl(R-BINAP)(R,R-DPEN) 200 89 36 RuHCl(R,R-DPPACH)(R,R-CYDN) 200 97 24RuHCl(R,R-DPPACH)(R,R-DPEN) 200 93 24

Example 1.9 Hydrogenation of 2-phenyl-3,4,5,6-tetrahydropyridine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 200 82 36RuHCl(R-BINAP)(R,R-DPEN) 200 76 36 RuHCl(R,R-DPPACH)(R,R-CYDN) 200 94 36RuHCl(R,R-DPPACH)(R,R-DPEN) 200 88 36

Example 1.10 Hydrogenation of N-(Benzylidene)propargylamine

Catalyst S:C Conv. (%) Time/hr RuHCl(R-BINAP)(R,R-CYDN) 1000 100 24RuHCl(R-BINAP)(R,R-DPEN) 1000 100 24 RuHCl(R,R-DPPACH)(R,R-CYDN) 1000100 24 RuHCl(R,R-DPPACH)(R,R-DPEN) 1000 100 24

Example 1.11 Hydrogenation of N-(1-Phenylethylidene)propargylamine

Conv. Catalyst S:C (%) Time/hr ee* RuHCl(R-BINAP)(R,R-CYDN) 1000 97 2478 (S) RuHCl(R-BINAP)(R,R-DPEN) 1000 100 24 67 (S)RuHCl(R,R-DPPACH)(R,R-CYDN) 1000 100 24 52 (S)RuHCl(R,R-DPPACH)(R,R-DPEN) 1000 100 24 51 (S)*The ee was determined from the rotation (α_(D)) of the de-protected1-phenylethylamine.

Example 2 Removal of the Protecting Group Example 2.1 Removal of theprotecting group from N-(Benzyl)propargylamine in Example 1.10

The procedure reported by Banerji et al. (Tetrahedron Lett. 1999, 40,767-770) was used to selectively remove the N-propargyl protectinggroup. A mixture of TiCl₃ (1.54 g, 10 mmol) and lithium (231 mg, 33mmol) was refluxed for 3 hours under argon in THF (40 ml). A solution ofN-(Benzyl)propargylamine (500 mg, 3.4 mmol) in THF (5 ml) was added tothe LVT reagent and stirred for 1 hour at room temperature. The reactionmixture was diluted with hexane-ethyl acetate mixture (70:30) andfiltered through celite. The filtrate washed with brine, dried (Na₂SO₄),and concentrated under vacuum. The crude product was purified usingchromatography (SiO₂) to yield benzylamine (245 mg, 66%).

Example 2.2 Removal of protecting group fromN-(1-Phenylethyl)propargylamine in Example 1.11

A solution of N-(1-Phenylethyl)propargylamine (500 mg, 3.1 mmol) in THF(5 ml) was added to the LVT reagent prepared as described in Example 2.1above, and the resulting mixture stirred for 2 hours at roomtemperature. The reaction mixture was diluted with hexane-ethyl acetatemixture (70:30) and filtered through celite. The filtrate washed withbrine, dried (Na₂SO₄), and concentrated under vacuum. The crude productwas purified using chromatography (SiO₂) to yield 1-phenylethylamine(290 mg, 77%). The rotation (α_(D)) of the de-protected1-phenylethylamine was used to determine the ee of the products inExample 1.11.

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety. Where a term in the present application is found to bedefined differently in a document incorporated herein by reference, thedefinition provided herein is to serve as the definition for the term.

1. A process for the hydrogenation and/or asymmetric hydrogenation of animine of Formula (I) to an amine of Formula (II):

wherein R¹ is selected from the group consisting of aryl and heteroaryl,which two groups are optionally substituted; R² is selected from thegroup consisting of hydrogen, aryl, heteroaryl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl andC₃₋₁₀heterocyclo, which latter eight groups are optionally substituted;and R³ is selected from the group consisting of optionally substitutedC₁ to C₂ alkyl and optionally substituted C₃₋₁₀cycloalkyl; or R¹ and R²or R² and R³ are linked to form an optionally substituted ring; whereinthe optional substituents of R¹ and R² are independently selected fromone or more of the group consisting of halo, NO₂, OR⁴, NR⁴ ₂ and R⁴, inwhich R⁴ is independently selected from one or more of the groupconsisting of hydrogen, aryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkenyl; R¹ is selected from the group consisting of aryl andheteroaryl, which two groups are optionally substituted; R² is selectedfrom the group consisting of hydrogen, aryl, heteroaryl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl andC₃₋₁₀heterocyclo, which latter eight groups are optionally substituted;and R³ is selected from the group consisting of optionally substitutedC₁ to C₂ alkyl and optionally substituted C₃₋₁₀cycloalkyl; or R¹ and R²or R² and R³ are linked to form an optionally substituted ring; whereinthe optional substituents of R¹ and R² are independently selected fromone or more of the group consisting of halo, NO₂, OR⁴, NR⁴ ₂ and R⁴, inwhich R⁴ is independently selected from one or more of the groupconsisting of hydrogen, aryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkenyl;
 2. A process for the hydrogenation and/or asymmetrichydrogenation of an imine of Formula (III) to an amine of Formula (IV):

wherein R⁴ and R⁵ represent simultaneously or independently hydrogen,aryl, heteroaryl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkenyl or C₃₋₁₀heterocyclo, which lattereight groups are optionally substituted, or R⁴ and R⁵ are linkedtogether to form an optionally substituted ring; R⁸ is selected from thegroup consisting of H, aryl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₁₀cycloalkyl and C₃₋₁₀cycloalkenyl, which latter six groups areoptionally substituted; wherein the optional substituents of R⁴, R⁵ andR⁶ are independently selected from one or more of the group consistingof halo, NO₂, OR⁷, NR⁷ ₂ and R⁷, in which R⁷ is independently selectedfrom the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl; andone or more of the carbon atoms in the alkyl, alkenyl and/or alkynylgroups of R⁴, R⁵ and/or R⁶ are optionally replaced with a heteroatomselected from the group consisting of O, S, N, P and Si, which, wherepossible, is optionally substituted with one or more C₁₋₆alkyl groups,said process comprising the steps of reacting imines of Formula (III) inthe presence of H₂, and a catalytic system in which the catalytic systemincludes a base and a ruthenium complex comprising (1) a diamine and (2)a diphosphine ligand or monodentate phosphine ligands.
 3. The processaccording to claim 1, wherein the amine of Formula (II) or its oppositeenantiomer, is produced in enantiomerically enriched form.
 4. Theprocess according to claim 2, wherein the amine of Formula (IV) or itsopposite enantiomer, is produced in enantiomerically enriched form. 5.The process according to claim 1, wherein R¹ is optionally substitutedaryl.
 6. The process according to claim 5, wherein R¹ is optionallysubstituted phenyl,
 7. The process according to claim 6, wherein R¹ isunsubstituted phenyl.
 8. The process according to of claim 5, wherein R²is selected from the group consisting of hydrogen, aryl, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl and C₃₋₆cycloalkenyl, whichlatter six groups are optionally substituted.
 9. The process accordingto claim 8, wherein R² is selected from the group consisting ofhydrogen, aryl and C₁₋₆alkyl, which latter two groups are optionallysubstituted.
 10. The process according to claim 9, wherein R² isselected from the group consisting of hydrogen, phenyl, and C₁₋₆alkyl,which latter two groups are optionally substituted.
 11. The processaccording to claim 10, wherein R² is selected from the group consistingof hydrogen, unsubstituted phenyl and methyl.
 12. The process accordingto claim 5, wherein R³ is selected from the group consisting ofoptionally substituted C₁ to C₂ alkyl and optionally substitutedC₃₋₆cycloalkyl.
 13. The process according to claim 12, wherein R³ ismethyl, ethyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, which latter four groups are unsubstituted.
 14. The processaccording to claim 1, wherein R² and R³, including the atoms to whichthey are attached, are linked to form an optionally substituted 5- or6-membered ring.
 15. The process according to claim 14, wherein R² andR³, including the atoms to which they are attached, are linked to forman unsubstituted 5- or 6-membered ring.
 16. The process according toclaim 5, wherein the optional substituents for R¹ and R² in thecompounds of Formula I, are independently selected from one or more ofthe group consisting of halo, NO₂, OR⁴, NR⁴ ₂ and R⁴, in which R⁴ isindependently selected from one or more of the group consisting ofhydrogen, aryl and C₁₋₄alkyl, and the optional substituents of R³ areindependently selected from one or more of the group consisting of halo,NO₂, OR⁵, NR⁵ ₂ and R⁵, in which R⁵ is independently selected from thegroup consisting of C₁₋₄alkyl.
 17. The process according to claim 16,wherein the optional substituents for R¹ and R² in the compounds ofFormula I, are independently selected from one or more of the groupconsisting of halo, NO₂, OH, OCH₃, NH₂, N(CH₃)₂, CH₃ and phenyl and theoptional substituents of R³ are independently selected from one or moreof the group consisting of halo, NO₂, OH, OCH₃, NH₂, N(CH₃)₂ and CH₃.18. The process according to claim 5, wherein one to three of the carbonatoms in the alkyl, alkenyl and/or alkynyl groups of R¹, R² and/or R³ isoptionally replaced with a heteroatom selected from the group consistingof O, S, N, NH and N—CH₃.
 19. The process according to claim 18, whereinsuitably one of the carbon atoms in the alkyl, alkenyl and/or alkynylgroups of R¹, R² and/or R³ is optionally replaced with a heteroatomselected from the group consisting of O, S, N, NH and N—CH₃.
 20. Theprocess according to claim 2, wherein R⁴ and R⁵ represent simultaneouslyor independently hydrogen, aryl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl or C₃₋₆cycloalkenyl, which latter six groups areoptionally substituted.
 21. The process according to claim 20, whereinR⁴ and R⁵ represent simultaneously or independently hydrogen, aryl orC₁₋₆alkyl, which latter two groups are optionally substituted.
 22. Theprocess according to claim 21, wherein R⁴ and R⁵ representsimultaneously or independently hydrogen, phenyl, and C₁₋₆alkyl, whichlatter two groups are optionally substituted.
 23. The process accordingto claim 22, wherein R⁴ and R⁵ represent simultaneously or independentlyhydrogen, unsubstituted phenyl or methyl.
 24. The process according toclaim 2, wherein R⁴ and R⁵, including the atoms to which they areattached, are linked to form an optionally substituted, suitablyunsubstituted, 5- or 6-membered ring.
 25. The process according to claim20, wherein R⁶ is selected from the group consisting of H, aryl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl andC₃₋₆cycloalkenyl, which latter six groups are optionally substituted.26. The process according to claim 25, wherein R⁶ is selected from thegroup consisting of H and C₁₋₄alkyl.
 27. The process according to claim26, wherein R⁶ is H.
 28. The process according to claim 20, wherein theoptional substituents for R⁴, R⁵ and R⁶, are independently selected fromone or more of the group consisting of halo, NO₂, OR⁷, NR⁷ ₂ and R⁷, inwhich R⁷ is independently selected from one or more of the groupconsisting of C₁₋₄alkyl.
 29. The process according to claim 28, whereinthe optional substituents for R⁴, R⁵ and R⁶ in the compounds of FormulaIII, are independently selected from one or more of the group consistingof halo, NO₂, OH, OCH₃, NH₂, N(CH₃)₂ and CH₃,
 30. The process accordingto claim 20, wherein one to three, of the carbon atoms in the alkyl,alkenyl and/or alkynyl groups of R⁴, R⁵ and/or R⁶ is optionally replacedwith a heteroatom selected from the group consisting of O, S, N, NH andN—CH₃.
 31. The process according to claim 30, wherein one of the carbonatoms in the alkyl, alkenyl and/or alkynyl groups of R⁴, R⁵ and/or R⁶ isoptionally replaced with a heteroatom selected from the group consistingof O, S, N, NH and N—CH₃.
 32. The process according to claim 1, whereinsaid ruthenium complex has the general Formula RuXY(PR₃)₂(NH₂—Z—NH₂)(III) or RuXY(R₂P—Q—PR₂)(NH₂—Z—NH₂) (IV), where Z and Q represent achiral or achiral linker; the ancilliary ligands PR₃ and R₂P—Q—PR₂represent monodentate and bidentate phosphines, respectively; and theligands X and Y represent an anionic ligand.
 33. The process accordingto claim 32, wherein the ligand PR₃:

represents a chiral or achiral monodentate phosphine ligand in which Ris simultaneously or independently selected from the group consisting ofoptionally substituted linear and branched alkyl containing 1 to 8carbon atoms, optionally substituted linear and branched alkenylcontaining 2 to 8 carbon atoms, optionally substituted cycloalkyl,optionally substituted aryl, OR and NR₂; or two R groups bonded to thesame P atom are bonded together to form a ring having 5 to 8 atoms andincluding the phosphorous atom to which said R groups are bonded. 34.The process according to claim 32, wherein the ligand R₂P—Q—PR₂:

represents a bidentate ligand in which R is simultaneously orindependently selected from the group consisting of optionallysubstituted linear and branched alkyl containing 1 to 8 carbon atoms,optionally substituted linear and branched alkenyl containing 2 to 8carbon atoms, optionally substituted cycloalkyl, optionally substitutedaryl, OR and NR₂; or two R groups bonded to the same P atom are bondedtogether to form a ring having 5 to 8 atoms and including thephosphorous atom to which said R groups are bonded; and Q is selectedfrom the group consisting of linear and cyclic C₂-C₇ alkylene,optionally substituted metallocenediyl and optionally substituted C₆-C₂₂arylene.
 35. The process according to claim 34, wherein the ligandR₂P—Q—PR₂ is chiral and includes atropisomeric bis-tertiary phosphines,in which the two phosphorus atoms are linked by a biaryl backbone. 36.The process according to claim 35, wherein the ligand R₂P—Q—PR₂ isselected from the group consisting of BINAP, BIPHEP and BIPHEMP.
 37. Theprocess according to claim 32, wherein the bidentate phosphine is achiral or achiral ligand of the type R₂P—NR⁸—Z—NR⁸—PR₂:

wherein each R, taken separately, is independently selected from thegroup consisting of optionally substituted linear and branched alkylcontaining 1 to 8 carbon atoms, optionally substituted linear andbranched alkenyl containing 2 to 8 carbon atoms, optionally substitutedcycloalkyl, optionally substituted aryl, OR and NR₂; or two R groupsbonded to the same P atom are bonded together to form a ring having 5 to8 atoms and including the phosphorous atom to which said R groups arebonded; each R⁸, taken separately, is independently selected from thegroup consisting of hydrogen, optionally substituted linear and branchedalkyl and alkenyl containing 1 to 8 carbon atoms, optionally substitutedcycloalkyl, optionally substituted aryl, OR and NR₂; and Z is optionallysubstituted linear and cyclic C₂-C₇ alkylene, optionally substitutedmetallocenediyl and optionally substituted C₆-C₂₂ arylene.
 38. Theprocess according to claim 37, wherein the ligand R₂P—NR⁸—Z—NR⁸—PR₂ isselected from the group consisting of DPPACH and DCYPPACH.
 39. Theprocess according to claim 1, wherein the diamine ligand has the FormulaNH₂—Z—NH₂:

wherein Z is selected from the group consisting of optionallysubstituted linear and cyclic C₂-C₇ alkylene, optionally substitutedmetallocenediyl and optionally substituted C₆-C₂₂ arylene.
 40. Theprocess according to claim 39, wherein the diamine ligand is chiral andincludes (1) compounds in which at least one of the amine-bearingcenters is stereogenic, (2) compounds in which both of the amine-bearingcenters are stereogenic and (3) atropisomeric bis-tertiary diamines, inwhich the two nitrogen atoms are linked by a biaryl backbone.
 41. Theprocess according to claim 39, wherein the diamine ligand NH₂—Z—NH₂ isselected from the group consisting of CYDN and DPEN.
 42. The processaccording to claim 1, wherein the diamine is a bidentate ligand of theFormula D—Z—NHR⁹ in which Z is selected from the group consisting ofoptionally substituted linear and cyclic C₂-C₇ alkylene, optionallysubstituted metallocenediyl and optionally substituted C₆-C₂₂ arylene; Dis an amido group donor or a chalcogenide radical selected from thegroup consisting of O, S, Se and Te; NHR⁶ is an amino group donor inwhich R⁹ is selected from the group consisting of hydrogen, optionallysubstituted linear and branched alkyl and alkenyl containing 1 to 8carbon atoms, optionally substituted cycloalkyl and optionallysubstituted aryl.
 43. The process according to claim 42, wherein D isNR¹⁰, wherein R¹⁰ is selected from the group consisting of S(O)₂R¹⁰,P(O)(R¹⁰)₂, C(O)R¹⁰, C(O)N(R¹⁰)₂ and C(S)N(R¹⁰)₂, in which R¹⁰ isindependently selected from the group consisting of hydrogen, optionallysubstituted linear and branched alkyl and alkenyl containing 1 to 8carbon atoms, optionally substituted cycloalkyl and optionallysubstituted aryl.
 44. The process according to claim 42, wherein thediamine is chiral and includes (1) compounds in which the amine-bearingcenter is stereogenic, (2) compounds in which both the donor-bearing (D)and amine-bearing centers are stereogenic.
 45. The process according toclaim 44, wherein the diamine is CH₃C₆H₄SO₃NCHPhCHPhNH₂.
 46. The processaccording to claim 1, wherein the ligands X and Y is selected from thegroup consisting of Cl, Br, I, H, hydroxy, alkoxy and acyloxy.
 47. Theprocess according to claim 1, wherein the base is an alcoholate or anhydroxide salt selected from the group consisting of compounds of theFormula (R¹²O)₂M′ and R¹²OM″, in which M′ is an alkaline-earth metal, M″is an alkaline metal and R¹² is selected from the group consisting ofhydrogen, C₁ to C₆ linear and branched alkyl.
 48. The process accordingto claim 1, wherein the base is an organic non-coordinating base. 49.The process according to claim 48, wherein the base is selected from thegroup consisting of DBU, NR₃ and phosphazene.
 50. The process accordingto claim 1, wherein the hydrogenation is carried out in the absence of asolvent.
 51. The process according to claim 1, wherein the hydrogenationreaction is carried out in the presence of a solvent.
 52. The processaccording to claim 51, wherein the solvent is selected from the groupconsisting of benzene, toluene, xylene, hexane, cyclohexane,tetrahydrofuran, primary and secondary alcohols, and mixtures thereof.53. The process according to claim 51, wherein the hydrogenation iscarried out in an amine solvent.
 54. A process for the preparation ofamines of Formula V from the amine of the Formula IV, or the oppositeenantiomer thereof:

wherein R⁴, R⁵ and R⁶ are as defined in claim 2, comprising reactingcompounds of Formula IV under conditions for the selective removal ofthe CH₂-C≡C—R⁶ group.
 55. The process according to claim 54, wherein theconditions for the selective removal of the CH₂—C≡C—R⁶ group compriseTiCl₃ and lithium.
 56. The process according to claim 54 wherein thecompound of Formula IV is enantiomericly enriched.